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Updated: Jan 13, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Integrative computational simulations and functional assays decode allosteric dysregulation in a pathogenic SIRT6
Haiyue Tang1, Jianyang Ao2, Guoyou Zhang3
1Shanghai Key Laboratory of Flexible Medical Robotics, Institute of Medical Robotics, Artificial Intelligence Clinical Research Center for Drug Discovery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China; School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; Department of Pharmaceutical and Artificial-Intelligence Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.
A colorectal cancer mutation (L197P) in SIRT6 protein destabilizes its structure, reducing its DNA repair and tumor suppression activity. This study reveals the structural mechanism behind impaired SIRT6 function in cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- SIRT6 is a key NAD+-dependent deacetylase involved in DNA repair, aging, and tumor suppression.
- Mutations in SIRT6 are found in various cancers, but their structural impact is poorly understood.
Purpose of the Study:
- To elucidate the structural mechanisms by which the L197P mutation in SIRT6 affects its catalytic activity.
- To understand the implications of SIRT6 dysfunction in colorectal cancer.
Main Methods:
- Molecular dynamics simulations to analyze the effect of L197P mutation on SIRT6 structure and dynamics.
- Markov state model analysis to identify conformational changes.
- Enzymatic assays to measure deacetylation efficiency.
Main Results:
- The L197P mutation destabilizes the substrate-binding loop (B-loop) of SIRT6, reducing substrate affinity.
- Simulations showed weakened interactions with acetylated substrates and increased catalytic distance.
- Markov state model analysis revealed a novel inactive conformation in the mutant.
- Enzymatic assays demonstrated a six-fold reduction in deacetylation efficiency for the L197P mutant.
Conclusions:
- The L197P mutation compromises SIRT6 function by altering its structure and reducing catalytic efficiency.
- These findings provide mechanistic insights into SIRT6 allosteric regulation and its role in tumorigenesis.
